Alkyl-xanthin derivative and process of making same.



UNITED STATES PATENT OEEIcE.

FRITZ AOH, OF MANNHEIM, GERMANY, ASSIGNOR TO 0. F. BOEHRINGER &

SOEHNE, OF WVALDI-IOF, GERMANY.

ALKYL- XANTHlN DERIVATIVE AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 631 ,7 58, dated August 22, 1899. Application filed February 18, 1898. Serial No. 670,848. (No specimens.)-

To all whom it may concern:

Be it known that I, FRITZ ACH, a citizen of the Empire of Germany, residing at Mannheim, in the Empire of Germany, have inven ted certain new and useful Improvements in the Art of Preparing Xanthins and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This invention relates to the manufacture of xanthins and their derivatives, and more particularly to the preparation of this class of bodies from alkylized uric acids.

In order to define more exactly the ground which this invention occupies in the art, it is tobe stated that a method has heretofore been found of obtaining the halogen derivatives of alkylized xanthins by the action of phosphorus chlorid thereon, the xanthins themselves being then obtained by reducing the halogen derivatives. This method has been set forth in United States patents to Emil Fischer, Nos. 569,489 and 569,490, dated October 13, 1896. According to these patents such conversion was, however, only possible for such alkyl-uric acids as contained two alkyl groups in the alloxan ring and whose structure would be represented by the general form ula (1 )RN OO (2) OO(5)CNH co s anN-c-nnm Adopting the nomenclature and system of numbering the carbon and nitrogen atoms of the purin nucleus which have been introduced by Emil Fischer and described in Be'richte der Deutschen Ohemt'schen Gese-ZZ- schaft, Vol. 30, page 549. That is to say, only other dimethyl-uric acids to halogen or chloroxanthins has hitherto been impossible. My investigations and experiments in this field have resulted in the discovery that all uric acids which have not been completely alkylized may be converted into the corresponding chloro-xanthins, provided no alkyl group has been bound to the nitrogen atom in the position 9. In the latter case only chloro-purins would result. This discovery demonstrates that, contrary to the opinion hitherto entertained, it is immaterial for the preparation of xanthins from uric acids whether the nitrogen atoms 1 and 3-01. 6., those in the alloxan ring-are alkyli'zed or not. All that is material in this respect is that the nitrogen atom 9 be not alkylized. I. have, moreover, ascertained as a result of my investigations that it is necessary to act upon the alkylized uric acid with phosphorus-oxychlorid alone in order to proceed to xanthins and that this result cannot be attained if the phosphorus-oxy-ohlorid acts on the alkyl-uric acid in conjunction with phosphorus-pentachlorid, for example. A comparison of the entirely and essentially different results obtained by acting on the same alkyl-u ric acid first with phosphorus-oxy-chlorid together with phosphorus-penta-chlorid, according to the methods heretofore known, and then with phosphorus-oxy-chlorid alone will serve admirablyto emphasize the essence of the present invention. Thus if, for example, 7-monomethyl-uric acid'is submitted to the joint action of phosphorus-oXy-ohlorid and phosphorus-penta-chlorid the oxygen, bound to the alloxan ring, alone is replaced by chlorin,

the resultant compound being 7-methyl-S-' If, however, phosphorus-oxy-chlorid alone is caused to react on 7-monomethyl-uric acid, chlorin is substituted for the oxygen occupying the position 8, whereby the xanthin derivative, 7 -methyl-2-6-dioXy-8-chlorop urin, or 7 -methyl-chloro-Xan thin is obtained:

Again, if 3-7-dimethyl-uric acid be treated with phosphorus-oXy-chlorid, together with phosphorus-penta-chlorid, there is formed 3 7 dimethyl 2-8 dioxy 6 chloropurin, as shown in Berichte der Deutschen Ohemischen Gesellschdft, Vol. 28, page2486, and Vol. 80, page 554: 4

chl-orid alone is caused to act upon the 3-7- dimethyl-uric acid, substitution of chlorin will again take place in the position 8 instead of in the alloXan-ring, the chloro-xanthin, 3- 7 -di'm'eth yl-2-6-dioXy-8-chloropurin or chlorotheobromin being formed:

I have found that the same result is obtained with other alkyl-uric acids, and in general my invention shows that the use of phosph-orus-oxy-chlorid alone results in the production of chloro-xan-thins when acting upon al kyl-uric acids which have no alkyl group bound to the N occupying the position 9, while the treatment of such uric acids with both phosphorus-penta-chlorid and the oxychlorid would result in chloropurins, which are not Ka n-thin derivatives.

According to my observations intermediate products, apparently containing phosphorus and chlorin, are at first formed when phosphorus-oxy-chlorid reacts upon alkylized uric acids, these intermediate bodies being subsequently changed into chloroxanthins by treatment with suitable means, such as alcohol or water, while phosphoric acid and hydrochloric acid are split off.

The chloro-Xanthins obtained under my invention are converted into higher alkylized products by employing the alkylizin g methods which are in use in connection with the uric acid and xanthi-n series. Thus, for example, ch-loro-theobromin may be obtained from 3- methyl-chloro-Xanthin on further methylation, the chloro-theobromin being in turn readily susceptible of conversion into'chlorocafiein by the same methods.

The chlorin -xanthins are converted into the correspondingxanthinsbyreducingmethods.

It is to be noted that under my invention other alkyl radicals than the methyl group maybe introduced into the Xanthin molecule. Thus the 3-methyl-chloro-Xanthin is readily converted into 3-methyl-1-7-diethyl-chloro- Xanthin by introducing the ethyl radical into the former.

For the purposes of'my invention it is unimportant whether the lower chloro-Xanthins are first alkylized and then reduced, or vice versa. In both ways I may proceed to the higher alkylized Xanthins, such as caffein.

In my application Serial No. 670,847, filed concurrently herewith,I have broadly covered the method above outlined of submitting alkyli-zed uric acids having no alkyl group in the position 9 to the action of phosphorusoXy-chlorid alone and subsequently reducing and alkyli'zing such products, said application also claiming specifically the application of such methods to 8-a'lkyl-uric acids. I do not therefore claim herein this method broadly; but my present invention'consists in the treatment of 7-alkyl-uric acids with phosphorusoXy-chlorid alone and in the subsequent reduction and alkylization methods applied to the resultant compound, which also forms a part of. my present invention.

My present invention, moreover, consists in such additional features and methods as will be fully set forth and pointed out in the claims.

In order to disclose my invention clearly and fully, I will now illustrate the same with a number of examples embodying the same.

1. Preparation of '7 -methyZ-2-6- diary-8- chloropmin or chZoro-heteroa rmthin from '7- meihg l-m'ic a'ct'(Z.One part, by weight, of dried and finely-powdered 7-monomethyluric acid is added to ten parts, by volume, of phosphorus-oxy-chlorid and boiled for from twenty-four to thirty hours with reflux. This treatment results in the solution of methyluric acid, a clear slightly-colored liquor being formed. This liquor is evaporated in uacuo and the tough varnish-like residue is taken up with warm alcohol. After boiling such solution a short time the chloro-hetero- Xanthin is thrown out in the form of a colorless crystalline mass, which is separated by filtration. This product is not quite pure, but is contaminated with some unchanged methyl-uric acid, which may be removed by boiling with much aceton, which dissolves the chloro-heterox anthin but-not themethyl-uric acid. The aceton solution isthen evaporated, and the resulting crystalline residue is taken up with dilute ammonia, treated with decolorizing carbon, and precipitated with dilute sulfuric acid. The 7 -methyl-chloro-xanthin or chloro-heteroxanthin is thereby obtained in the form of colorless short prismatic crystals, which give figures corresponding to the formula O H N O Cl. Its structural formulais TIN- C0 O0 ()NCI-I cm I-lNO-N as is shown by its conversion into chloro-caffein. (See II 1 b.)

The chloro-heteroxanthin or 7-methyl-2-6- dioxy-S-chloropurin is formed about according to the equation:

nN-co 3 O0 (J NCH +POCI That this new product is axanthin derivative is also corroborated by the fact that it gives the murexid test with chlorin-water or dilute nitric acid. From boiling water, in which it is moderately soluble, it crystallizes in short needles, which are frequently aggregated in bunches. It is soluble with difficulty in alcohol and aceton and with very great difficulty in benzene or chloroform. It is readily taken up by dilute alkalies, ammonia, and soda or potash (carbonates) solutions. An ammoniacal solution of the same added to an ammoniacalsilver solution gives rise to a colorless silver salt consisting of fine needles, which salt remains unchanged on boiling.

Chloro-heteroxanthin has no melting-point; but on being heated rapidly it becomes yellow at about 300 centigrade and is decomposed at about 340 centigrade, the decomposition being attended by dark-brown eoloration and effervescence.

2. Preparation of chloro-caflein from '7- methyl chloro a anthin.Three parts, by weight, of 7 -methylchloro-xanthin or chloroheteroxanthin, which has been hereinbefore described, are dissolved in eighteen parts, by volume, double-normal caustic potash lye (potassium-hydrate) and thirty-six parts, by volume, of water, and after adding thereto five parts, by weight, of methyl-iodid the same is heated to centigrade in the pressure-tube, this temperature being maintained for two and one-half hours and the mass being constantly agitated. After allowing the same to cool the resultant chloro-caffein will be found to exist in the tube in the form of a paste or pulp. It is isolated, as set forth under 11 1 a in my concurrent application hereinabove referred tothat is to say, by extracting the balance of non-precipitated chlorocaifein from the lyes, which have been rendered slightly alkaline by a suitable solvent-such, for example, as chloroform. The whole product is then purified by once recrystallizing from water.

The conversion of chloro-heteroxanthin or 7-methyl-chloro-xanthin into 1-3-7-methyl-S- chloro-Xanthin or chloro-caifein takes place according to the equation:

oc o nxnn+enr mno coi mnN-o-N The practical yield is equivalent to the theoretieal an d the chloro-caifein is obtained pure.

3. Preparation of 7-methyl-Q-d-d ioccypm'in 0r heteroxanthin from 7-methyl-8-chlor0- ocanthin.lf one part, by weight, of 7-methylchloro-xanthin, described under 1 be heated on the water-bath, together with eight times its weight of fuming hydriodic acid of the specific gravity 1.96, phosphonium-iodid being added from time to time to the mixture, a clear colorless solution is soon formed,

whereby the end of the reaction is indicated.

The reaction proceeds according to the equation:

HN-CO oo CQNOHQ-HL:

i ll.

oo o-ncn aaua 0.11 I l I'INUN The resulting liquid is evaporated to dryness and the residue is repeatedly dissolved in water and evaporated to completely remove the hydriodic acid. The crystalline residue is then suspended in about twenty parts of hot water,and soda-lye (sodium-hydrate) is added until complete solution is effected, when it is allowed to cool. On cooling the characteristic difficultly-soluble sodium salt of heterofianthin is thrown out in the form of coarse colorless crystals. This reaction is expressed in the equation: 7

I oo c-non +Na0ll:

011 I-IN C-N HN- G The heteroxanthin may then be liberated from the sodium salt by dissolving in hot water, supersaturating the aqueous solution with acetic acid and separating the heteroxanthin by filtration. The heteroxanthin s0 obtained possesses all the characteristic properties enumerated in Emil Fischers application filed September 7,1897, Serial No. 650,826.

The chloro-caffein obtained under my present invention may be converted into cafiein according to well-known reducing methods. Oaffein or theobromin may also be obtained by further methylizing' the heteroxanthin.

It will thus be seen that the new compound, 7-methyl-8-chloroxanthin or chloro-heteroe xanthin, obtained under my invention issusceptible of conversion into a higher methyl- .ized Xanthin by first alkylizing and then rereflux in the proportions and for the time substantially as set forth, then evaporating the resultant liquor and taking up the residue'f with alcohol, then boiling and separating the resultant crystalline mass by filtration.

- 4. In the art of preparing Xanthins, the

.fore given, which is moderately soluble in boiling water, sol u'ble-with' difficulty in alco- :hol, aceton, benzol and chloroform, and readily soluble in dilute alkalies, including ammonia, soda and potash solutions, which crys tallizes in colorless, short prisms and which has no melting-point but, on being heated to about 300, centigrade, turns yellow and'decomposes at about 340, centigrade,with darkbrown coloration and effervescence.

6. The process which consists in treating chloro-heteroxanthin with alkylizing agents.

7. The process which consists in dissolving chloro-heteroxanthin in caustic-potash lye and adding thereto an alkyl-halogen compound and heating the mixture.

8. The process which consists in dissolving chloro-heteroxanthin in caustic-potash lye and adding thereto methyl-iodid and heating the same under pressure while agitating the mixture, all in the proportions and under the conditions, substantially as specified.

9. The process which consists in submitting chloro-heteroxanthin to alkylization and reduction.

10. The process which consists in treating 7-alky1-uric acid With'phosphorus-oxy-chlorid alone and isolating the resultant 'Z-alkylchloro-xanthin and then submitting the same to alkylizing and reducing agents.

11. The process which consists in.- heating '7 -methyl-uric acid with phosphorus-oXy-chlorid, then isolating the resultantchloro-xanthin and inethylating the same, and finally reducing themethylized product.

In testimony whereof I aflix my signature in presence of two witnesses.

FRITZ ACH. Vitnesses:

LORENZ AoH, JACOB ADRIAN. 

